The survival of Leishmania depends upon their ability to evade the microbicidal activity of macrophages. We have defined two mechanisms by which the parasite excapes macrophages mediated killing. First, certain strains are resistant to lymphokine (LK)-mediated activated macrophage killing. These parasites are located at one end of a spectrum in susceptibility to macrophage killing of strains belonging to the Genus Leishmania. The second manner by which parasites escape killing is by residing in the skin. We have found that at cutaneous temperatures, which range between 28 C and 33 C, macrophages display an impaired capacity to kill Leishmania. In order to better understand both of these phenomena, we investigated the mechanism(s) used by macrophages to kill Leishmania parasites. We found that the macrophage cell line, IC-21, was incapable of producing oxygen metabolites often associated with killing. Nevertheless, LK-activated IC-21 cells killed Leishmania, suggesting that oxygen metabolites are not required to kill Leishmania. We are presently studying a cytolytic factor derived from these cells that may be responsible for mediating macrophage microbicidal activity. In a related project, we have been attempting to define the antigens involved in the induction of protective immunity with a non-living L. tropica vaccine. We have identified protective parasite fractions. An analysis of the antigens recognized by protected and non-protected mice revealed that certain antigens were associated with protection. We are presently using both conventional and DNA recombinant technology to further identify these protective antigens. In addition, we are using these antigens to define the immunologic mechanisms responsible for protection in vaccine mice.